2-((2-thioxo-2,3-dihydro-1H-imidazol-4-yl)methyl)-3,4-dihydronaphthalen-1(2H)-one

ABSTRACT

A compound of the formula 
                         
or a pharmaceutically acceptable salt thereof, is disclosed herein. Methods and compositions related thereto are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of application Ser. No.11/368,990, filed on Mar. 6, 2006, now U.S. Pat. No. 7,358,259 which iscontinuation-in-part of application serial number 10/437,807 filed onMay 14, 2003, which is a continuation-in-part of application Ser. No.10/153,328 filed on May 21, 2002 now abandoned.

BACKGROUND OF THE INVENTION Background

Human adrenergic receptors are integral membrane proteins which havebeen classified into two broad classes, the alpha and the betaadrenergic receptors. Both types mediate the action of the peripheralsympathetic nervous system upon binding of catecholamines,norepinephrine and epinephrine.

Norepinephrine is produced by adrenergic nerve endings, whileepinephrine is produced by the adrenal medulla. The binding affinity ofadrenergic receptors for these compounds forms one basis of theclassification: alpha receptors tend to bind norepinephrine morestrongly than epinephrine and much more strongly than the syntheticcompound isoproterenol. The preferred binding affinity of these hormonesis reversed for the beta receptors. In many tissues, the functionalresponses, such as smooth muscle contraction, induced by alpha receptoractivation are opposed to responses induced by beta receptor binding.

Subsequently, the functional distinction between alpha and betareceptors was further highlighted and refined by the pharmacologicalcharacterization of these receptors from various animal and tissuesources. As a result, alpha and beta adrenergic receptors were furthersubdivided into alpha₁, α₂, β₁, and β₂ subtypes. Functional differencesbetween α₁ and α₂ receptors have been recognized, and compounds whichexhibit selective binding between these two subtypes have beendeveloped. Thus, in published international patent application WO92/0073, the selective ability of the R(+) enantiomer of terazosin toselectively bind to adrenergic receptors of the α₁ subtype was reported.The α₁/α₂ selectivity of this compound was disclosed as beingsignificant because agonist stimulation of the α₂ receptors was said toinhibit secretion of epinephrine and norepinephrine, while antagonism ofthe α₂ receptor was said to increase secretion of these hormones. Thus,the use of non-selective alpha-adrenergic blockers, such asphenoxybenzamine and phentolamine, was said to be limited by their α₂adrenergic receptor mediated induction of increased plasma catecholamineconcentration and the attendant physiological sequelae (increased heartrate and smooth muscle contraction).

The cloning, sequencing and expression of alpha receptor subtypes fromanimal tissues has led to the subclassification of the α₁adrenoreceptors into α_(1A), α_(1B), and α_(1D). Similarly, the α₂adrenoreceptors have also been classified α_(2A), α_(2B), and α_(2C)receptors. Each α₂ receptor subtype appears to exhibit its ownpharmacological and tissue specificities. Compounds having a degree ofspecificity for one or more of these subtypes may be more specifictherapeutic agents for a given indication than an α₂ receptorpan-agonist (such as the drug clonidine) or a pan-antagonist.

Among other indications, such as the treatment of glaucoma,hypertension, sexual dysfunction, and depression, certain compoundshaving alpha 2 adrenergic receptor agonist activity are knownanalgesics. However, many compounds having such activity do not providethe activity and specificity desirable when treating disorders modulatedby alpha-2 adrenoreceptors. For example, many compounds found to beeffective agents in the treatment of pain are frequently found to haveundesirable side effects, such as causing hypotension and sedation atsystemically effective doses. There is a need for new drugs that providerelief from pain without causing these undesirable side effects.Additionally, there is a need for agents which display activity againstpain, particularly chronic pain, such as chronic neuropathic andvisceral pain.

British Patent 1 499 485, published Feb. 1, 1978 describes certainthiocarbamide derivatives; some of these are said to be useful in thetreatment of conditions such as hypertension, depression or pain.

PCT Publications WO01/00586 published on Jan. 4, 2002 and WO99/28300published on Jun. 10, 1999 describe certain imidazole derivatives actingas agonists of alpha_(2B) and/or alpha_(2C) adrenergic receptors. U.S.Pat. No. 6,313,172 discloses phenylmethyl-thiourea derivatives used fortreatment of pain.

U.S. Pat. No. 4,798,843 describes (phenyl)-imidazole-2-thiones andsubstituted (phenyl)-imidazole-2-thiones.

U.S. Pat. Nos. 6,545,182 and 6,313,172 describephenylmethyl-(2hydroxy)ethylthioureas which have no significantcardiovascular or sedative effects and are useful for alleviatingchronic pain and allodynia. U.S. Pat. No. 6,534,542 describescycloalkyl, cycloalkenyl, cycloalkylmethyl and cycloalkenylmethyl(2-hydroxy)ethylthioureas and their use as specific or selectiveagonists of alpha_(2B) adrenergic receptors. In a different biologicalor pharmaceutical context United States Published Application20020094998, published on Jul. 18 2002 and claiming priority of U.S.Provisional Application No. 6/0244,850 discloses a compound withoutassigning the proper stereochemistry to it, which corresponds to twocompounds described in the present application with the properstereochemistry.

DESCRIPTION OF THE INVENTION

One embodiment is a compound of Formula 1

or a pharmaceutically acceptable salt thereof.

Another embodiment is a composition comprising a racemic mixture of thecompound of Formula I.

Another embodiment is a composition consisting essentially of asubstantially pure racemic mixture of the compound of Formula I.

Another embodiment is a composition comprising the S-enantiomer of thecompound of Formula I.

Another embodiment is a composition consisting essentially of asubstantially pure S-enantiomer of the compound of Formula I.

Another embodiment is a composition having an enantiomeric excess of anR-enantiomer of the compound of Formula I.

Another embodiment is a composition consisting essentially of asubstantially pure R-enantiomer of the compound of Formula I.

Another embodiment is a composition comprising a mixture of enantiomersof the compound of Formula I. having (+) optical activity.

Another embodiment is a composition consisting essentially of asubstantially pure (+)-entantiomer of the compound of Formula I.

Another embodiment is a composition comprising a mixture of enantiomersof the compound of Formula I. having (−) optical activity.

Another embodiment is a composition consisting essentially of asubstantially pure (−) -entantiomer of the compound of Formula I.

One embodiment is a compound comprising2-((2-thioxo-2,3-dihydro-1H-imidazol-4-yl)methyl)-3,4-dihydronaphthalen-1(2H)-one,or a pharmaceutically acceptable salt thereof.

Another embodiment is a composition comprising a racemic mixture of saidcompound.

Another embodiment is a composition consisting essentially of asubstantially pure racemic mixture of said compound.

Another embodiment is a composition comprising the S-enantiomer of saidcompound.

Another embodiment is a composition consisting essentially of asubstantially pure S-enantiomer of said compound.

Another embodiment is a composition having an enantiomeric excess of anR-enantiomer of said compound.

Another embodiment is a composition consisting essentially of asubstantially pure R-enantiomer of said compound.

Another embodiment is a composition comprising a mixture of enantiomersof said compound having (+) optical activity.

Another embodiment is a composition consisting essentially of asubstantially pure (+)-entantiomer of said compound.

Another embodiment is a composition comprising a mixture of enantiomersof said compound having (−) optical activity.

Another embodiment is a composition consisting essentially of asubstantially pure (−)-entantiomer of said compound.

Other embodiments are pharmaceutical compositions containing as theactive ingredient one or more compounds of Formula 1, the compositionsbeing utilized as medicaments in mammals, including humans, fortreatment of diseases and or alleviations of conditions which areresponsive to treatment by agonists of alpha_(2B) adrenergic receptors.The compositions containing the compounds disclosed herein areprimarily, but not exclusively, used for alleviation of chronic painand/or allodynia. The compounds have the demonstrable advantageousproperty that they are specific or selective to alpha_(2B) and/oralpha_(2C) adrenergic receptors in preference over alpha_(2A) adrenergicreceptors, and as such have no or only minimal cardiovascular and/orsedatory activity.

It will be readily apparent to those skilled in the art that

Imidazole-2-thiones can undergo tautomeric transformations and can bedepicted by the tautomeric formulas shown below. All tautomers ofFormula 1 are within the scope of the invention.

TABLE 1

EC₅₀ (nM) (intrinsic activity) Compound # Alpha 2A Alpha 2B Alpha 2C

NA 41 (0.83) NA

NA 92 (0.79) NA

Biological Activity, Modes of Administration

The compounds disclosed herein are agonists of alpha₂ adrenergicreceptors, particularly they tend to be specific or selective agonistsof alpha_(2B) and/or to a lesser extent alpha_(2C) adrenergic receptors,in preference over alpha_(2A) adrenergic receptors. The specific orselective alpha_(2B) and/or to a lesser extent alpha_(2C) agonistactivity of the disclosed compounds is demonstrated in an assay titledReceptor Selection and Amplification technology (RSAT) assay, which isdescribed in the publication by Messier et. Al., 1995, Pharmacol.Toxicol. 76, pp. 308-311 (incorporated herein by reference) and is alsodescribed below. Another reference pertinent to this assay is Conklin etal. (1993) Nature 363:274-6, also incorporated herein by reference.

Receptor Selection and Amplification Technology (RSAT) Assay

The RSAT assay measures a receptor-mediated loss of contact inhibitionthat results in selective proliferation of receptor-containing cells ina mixed population of confluent cells. The increase in cell number isassessed with an appropriate transfected marker gene such asβ-galactosidase, the activity of which can be easily measured in a96-well format. Receptors that activate the G protein, Gq, elicit thisresponse. Alpha₂ receptors, which normally couple to G_(i), activate theRSAT response when coexpressed with a hybrid Gq protein that has a G_(i)receptor recognition domain, called Gq/i5.

NIH-3T3 cells are plated at a density of 2×10⁶ cells in 15 cm dishes andmaintained in Dulbecco's modified Eagle's medium supplemented with 10%calf serum. One day later, cells are cotransfected by calcium phosphateprecipitation with mammalian expression plasmids encodingp-SV-β-galactosidase (5-10 μg), receptor (1-2 μg) and G protein (1-2μg). 40 μg salmon sperm DNA may also be included in the transfectionmixture. Fresh media is added on the following day and 1-2 days later,cells are harvested and frozen in 50 assay aliquots. Cells are thawedand 100 μl added to 100 μl aliquots of various concentrations of drugsin triplicate in 96-well dishes. Incubations continue 72-96 hr at 37 EC.After washing with phosphate-buffered saline, β-galactosidase enzymeactivity is determined by adding 200 μl of the chromogenic substrate(consisting of 3.5 mM o-nitrophenyl-β-D-galactopyranoside and 0.5%nonidet P-40 in phosphate buffered saline), incubating overnight at 30EC and measuring optical density at 420 nm. The absorbance is a measureof enzyme activity, which depends on cell number and reflects areceptor-mediated cell proliferation. The EC₅₀ and maximal effect ofeach drug at each alpha₂ receptor is determined. The efficacy orintrinsic activity is calculated as a ratio of the maximal effect of thedrug to the maximal effect of a standard full agonist for each receptorsubtype. Brimonidine, also called UK14304, the chemical structure ofwhich is shown below, is used as the standard agonist for thealpha_(2A), alpha_(2B) and alpha_(2C) receptors.

The results of the RSAT assay with several exemplary compounds aredisclosed in Table 1 above together with the chemical formulas of theseexamplary compounds. Each number in the table represents EC₅₀ innanomolar (nM) concentration whereas the number in parenthesis in thetable shows the fraction of activity of the appropriate standard whichis attained by the tested compound. NA stands for “not active” atconcentrations less than 10 micromolar. As is known EC₅₀ is theconcentration at which half of a given compound's maximal activity isobserved.

Generally speaking alpha2 agonists, can alleviatesympathetically-sensitized conditions that are typically associated withperiods of stress. These include 1) the increased sensitivity to stimulisuch as intracranial pressure, light and noise characteristic ofmigraines and other headaches; 2) the increased sensitivity to colonicstimuli characteristic of Irritable Bowel Syndrone and other GIdisorders such as functional dyspepsia; 3) the sensation of itchassociated with psoriasis and other dermatological conditions; 4) muscletightness and spasticity; 5) sensitivity to normally innocuous stimulisuch as light touch and spontaneous pain characteristic of conditionslike fibromyalgia; 6) various cardiovascular disorders involvinghypertension, tachycardia, cardiac ischemia and peripheralvasoconstriction; 7) metabolic disorders including obesity and insulinresistance; 8) behavioral disorders such as drug and alcohol dependence,obsessive-compulsive disorder, Tourette's syndrome, attention deficitdisorder, anxiety and depression; 9) altered function of the immunesystem such as autoimmune diseases including lupus erythematosis and dryeye disorders; 10) chronic inflammatory disorders such as Crohn'sdisease and gastritis; 11) sweating (hyperhydrosis) and shivering; and12) sexual dysfunction.

Alpha2 agonists including alpha2B/2C agonists are also useful in thetreatment of glaucoma, elevated intraocular pressure, neurodegenerativediseases including Alzheimer's, Parkinsons, ALS, schizophrenia, ischemicnerve injury such as stroke or spinal injury, and retinal injury asoccurs in glaucoma, macular degeneration, diabetic retinopathy, retinaldystrophies, Lebers optic neuropathy, other optic neuropathies, opticneuritis often associated with multiple sclerosis, retinal veinocclusions, and following procedures such as photodynamic therapy andLASIX. Also included are chronic pain conditions such as cancer pain,post-operative pain, allodynic pain, neuropathic pain, CRPS orcausalgia, visceral pain.

A compound is considered selective agonist of alpha_(2B) and/oralpha_(2C) adrenergic receptors in preference over alpha_(2A) receptors,if the compound is at least ten (10) times more active towards eitheralpha_(2B) or towards alpha_(2C) receptors than towards alpha_(2A)receptors. It can be seen from these tables that the disclosed compoundsare specific or selective agonists of alpha_(2B) and/or alpha_(2C)adrenergic receptors within the former definition, and in fact have noagonist like activity or only insignificant agonist-like activity onalpha_(2A) receptors.

Thus, the disclosed compounds are useful for treating conditions anddiseases which are responsive to treatment by alpha_(2B) and/oralpha_(2C) adrenergic receptor agonists. Such conditions and diseasesinclude, but are not limited to, pain including chronic pain (which maybe, without limitation visceral, inflammatory, referred or neuropathicin origin) neuropathic pain, corneal pain, glaucoma, reducing elevatedintraocular pressure, ischemic neuropathies and other neurodegenerativediseases, diarrhea, and nasal congestion. Chronic pain may arise as aresult of, or be attendant to, conditions including without limitation:arthritis, (including rheumatoid arthritis), spondylitis, goutyarthritis, osteoarthritis, juvenile arthritis, and autoimmune diseasesincluding without limitation, lupus erythematosus. Visceral pain mayinclude, without limitation, pain caused by cancer or attendant to thetreatment of cancer as, for example, by chemotherapy or radiationtherapy. In addition, the disclosed compounds are useful for treatingmuscle spasticity including hyperactive micturition, diuresis,withdrawal syndromes, neurodegenerative diseases including opticneuropathy, spinal ischemia and stroke, memory and cognition deficits,attention deficit disorder, psychoses including manic disorders,anxiety, depression, hypertension, congestive heart failure, cardiacischemia and nasal congestion, chronic gastrointestinal inflammations,Crohn's disease, gastritis, irritable bowel syndrome (IBS), functionaldyspepsia and ulcerative colitis.

The activity of the disclosed compounds is highly advantageous becausethe administration of these compounds to mammals does not result insedation or in significant cardiovascular effects (such as changes inblood pressure or heart rate).

The disclosed compounds act and can be used as a highly effectiveanalgesic, particularly in chronic pain models, with minimal undesirableside effects, such as sedation and cardiovascular depression, commonlyseen with other agonists of the α₂ receptors.

The disclosed compounds may be administered at pharmaceuticallyeffective dosages. Such dosages are normally the minimum dose necessaryto achieve the desired therapeutic effect; in the treatment of chronicpain, this amount would be roughly that necessary to reduce thediscomfort caused by the pain to tolerable levels. Generally, such doseswill be in the range 1-1000 mg/day; more preferably in the range 10 to500 mg/day. However, the actual amount of the compound to beadministered in any given case will be determined by a physician takinginto account the relevant circumstances, such as the severity of thepain, the age and weight of the patient, the patient's general physicalcondition, the cause of the pain, and the route of administration.

The compounds are useful in the treatment of pain in a mammal;particularly a human being. Preferably, the patient will be given thecompound orally in any acceptable form, such as a tablet, liquid,capsule, powder and the like. However, other routes may be desirable ornecessary, particularly if the patient suffers from nausea. Such otherroutes may include, without exception, transdermal, parenteral,subcutaneous, intranasal, intrathecal, intramuscular, intravenous, andintrarectal modes of delivery. Additionally, the formulations may bedesigned to delay release of the active compound over a given period oftime, or to carefully control the amount of drug released at a giventime during the course of therapy.

Also disclosed are therapeutic compositions comprising the compounds ofFormula 1 and pharmaceutically acceptable salts of these compounds and apharmaceutically acceptable excipient. Such an excipient may be acarrier or a diluent; this is usually mixed with the active compound, orpermitted to dilute or enclose the active compound. If a diluent, thecarrier may be solid, semi-solid, or liquid material that acts as aexcipient or vehicle for the active compound. The formulations may alsoinclude wetting agents, emulsifying agents, preserving agents,sweetening agents, and/or flavoring agents. If used as in an ophthalmicor infusion format, the formulation will usually contain one or moresalt to influence the osmotic pressure of the formulation.

Also disclosed are methods for the treatment of pain, particularlychronic pain, through the administration of one or more compounds ofFormula 1 or pharmaceutically acceptable salts thereof to a mammal inneed thereof. As indicated above, the compound will usually beformulated in a form consistent with the desired mode of delivery.

It is known that chronic pain (such as pain from cancer, arthritis, andmany neuropathic injuries) and acute pain (such as that pain produced byan immediate mechanical stimulus, such as tissue section, pinch, prick,or crush) are distinct neurological phenomena mediated to a large degreeeither by different nerve fibers and neuroreceptors or by arearrangement or alteration of the function of these nerves upon chronicstimulation. Sensation of acute pain is transmitted quite quickly,primarily by afferent nerve fibers termed C fibers, which normally havea high threshold for mechanical, thermal, and chemical stimulation.While the mechanisms of chronic pain are not completely understood,acute tissue injury can give rise within minutes or hours after theinitial stimulation to secondary symptoms, including a regionalreduction in the magnitude of the stimulus necessary to elicit a painresponse. This phenomenon, which typically occurs in a region emanatingfrom (but larger than) the site of the original stimulus, is termedhyperalgesia. The secondary response can give rise to profoundlyenhanced sensitivity to mechanical or thermal stimulus.

The A afferent fibers (Aβ and Aδ fibers) can be stimulated at a lowerthreshold than C fibers, and appear to be involved in the sensation ofchronic pain. For example, under normal conditions, low thresholdstimulation of these fibers (such as a light brush or tickling) is notpainful. However, under certain conditions such as those following nerveinjury or in the herpes virus-mediated condition known as shingles theapplication of even such a light touch or the brush of clothing can bevery painful. This condition is termed allodynia and appears to bemediated at least in part by Aβ afferent nerves. C fibers may also beinvolved in the sensation of chronic pain, but if so it appears clearthat persistent firing of the neurons over time brings about some sortof change which now results in the sensation of chronic pain.

By “acute pain” is meant immediate, usually high threshold, pain broughtabout by injury such as a cut, crush, burn, or by chemical stimulationsuch as that experienced upon exposure to capsaicin, the activeingredient in chili peppers.

By “chronic pain” is meant pain other than acute pain, such as, withoutlimitation, neuropathic pain, visceral pain (including that broughtabout by Crohn's disease and irritable bowel syndrome (IBS)), andreferred pain. The following in vivo assays can be employed todemonstrate the biological activity of the compounds.

Sedative Activity

To test sedation, six male Sprague-Dawley rats are given up to 3 mg/kgof the test compound in a saline or DMSO vehicle by intraperitonealinjection (i.p.). Sedation is graded 30 minutes following administrationof the drug by monitoring locomotor skills as follows.

The Sprague-Dawley rats are weighed and 1 ml/kg body weight of anappropriate concentration (ie. 3 mg/ml for a final dose of 3 mg/kg) drugsolution is injected intraperitoneally. Typically the test compound isformulated in approximately 10 to 50% DMSO. The results are compared tocontrols that are injected with 1 ml/kg saline or 10 to 50% DMSO. Ratactivity is then determined 30 minutes after injection of the drugsolution. Rats are placed in a dark covered chamber and a digicomanalyzer (Omnitech Electronic) quantitates their exploratory behaviorfor a five-minute period. The machine records each time the ratinterrupts an array of 32 photoelectric beams in the X and Yorientation.

Effects on Cardiovascular System

To test the effect of the compounds on the cardiovascular system,typically six cynomolgus monkeys are given 500 μg/kg of the testcompound by intravenous injection (i.v.) Or 3 mg/kg by oral gavage. Theeffects of the compound on the animals' blood pressure and heart rate ismeasured at time intervals from 30 minutes to six hours followingadministration of the drug. The peak change from a baseline measurementtaken 30 minutes before drug administration is recorded using a bloodpressure cuff modified for use on monkeys.

Specifically and typically the monkeys are weighed (approximately 4 kg)and an appropriate volume (0.1 ml/kg) of a 5 mg/ml solution of the testcompound formulated in 10 to 50% DMSO is injected into the cephalic veinin the animals' arm. Cardiovascular measurements are made with a BP 100Sautomated sphygmomanometer (Nippon Colin, Japan) at 0.5, 1, 2, 4 and 6hours.

The results of this test show that the compounds of disclosed hereinhave no or only minimal detectable effect on the cardiovascular system.

Alleviation of Acute Pain

Models to measure sensitivity to acute pain have typically involved theacute application of thermal stimuli; such a stimulus causes aprogrammed escape mechanism to remove the affected area from thestimulus. The proper stimulus is thought to involve the activation ofhigh threshold thermoreceptors and C fiber dorsal root ganglion neuronsthat transmit the pain signal to the spinal cord.

The escape response may be “wired” to occur solely through spinalneurons, which receive the afferent input from the stimulated nervereceptors and cause the “escape” neuromuscular response, or may beprocessed supraspinally—that is, at the level of the brain. A commonlyused method to measure nociceptive reflexes involves quantification ofthe withdrawal or licking of the rodent paw following thermalexcitation. See Dirig, D. M. et al., J. Neurosci. Methods 76:183-191(1997) and Hargreaves, K. et al., Pain 32:77-88 (1988), herebyincorporated by reference herein.

In a variation of this latter model, male Sprague-Dawley rats are testedby being placed on a commercially available thermal stimulus deviceconstructed as described in Hargreaves et al. This device consists of abox containing a glass plate. The nociceptive stimulus is provided by afocused projection bulb that is movable, permitting the stimulus to beapplied to the heel of one or both hindpaws of the test animal. A timeris actuated with the light source, and the response latency (defined asthe time period between application of the stimulus and an abruptwithdrawal of the hindpaw) is registered by use of a photodiode motionsensor array that turns off the timer and light. Stimulus strength canbe controlled by current regulation to the light source. Heating isautomatically terminated after 20 seconds to prevent tissue damage.

Typically four test animals per group are weighed (approximately 0.3 kg)and injected intraperitonealy (i.p.) with 1 ml/kg of the test compoundformulated in approximately 10 to 50% dimethylsulfoxide (DMSO) vehicle.Animals typically receive a 0.1 mg/kg and a 1 mg/kg dose of the threecompounds. Rats are acclimated to the test chamber for about 15 minutesprior to testing. The paw withdrawal latency is measured at 30, 60 and120 minutes after drug administration. The right and left paws aretested 1 minute apart, and the response latencies for each paw areaveraged. Stimulus intensity is sufficient to provide a temperature of45-50 degrees centigrade to each rat hindpaw.

Alleviation of Chronic Pain

A model in accordance with Kim and Chung 1992, Pain 150, pp 355-363(Chung model), for chronic pain (in particular peripheral neuropathy)involves the surgical ligation of the L5 (and optionally the L6) spinalnerves on one side in experimental animals. Rats recovering from thesurgery gain weight and display a level of general activity similar tothat of normal rats. However, these rats develop abnormalities of thefoot, wherein the hindpaw is moderately everted and the toes are heldtogether. More importantly, the hindpaw on the side affected by thesurgery appears to become sensitive to pain from low-thresholdmechanical stimuli, such as that producing a faint sensation of touch ina human, within about 1 week following surgery. This sensitivity tonormally non-painful touch is called “tactile allodynia” and lasts forat least two months. The response includes lifting the affected hindpawto escape from the stimulus, licking the paw and holding it in the airfor many seconds. None of these responses is normally seen in thecontrol group.

Rats are anesthetized before surgery. The surgical site is shaved andprepared either with betadine or Novacaine. Incision is made from thethoracic vertebra Xlll down toward the sacrum. Muscle tissue isseparated from the spinal vertebra (left side) at the L4-S2 levels. TheL6 vertebra is located and the transverse process is carefully removedwith a small rongeur to expose the L4-L6 spinal nerves. The L5 and L6spinal nerves are isolated and tightly ligated with 6-0 silk thread. Thesame procedure is done on the right side as a control, except noligation of the spinal nerves is performed.

A complete hemostasis is confirmed, then the wounds are sutured. A smallamount of antibiotic ointment is applied to the incised area, and therat is transferred to the recovery plastic cage under a regulatedheat-temperature lamp. On the day of the experiment, at least seven daysafter the surgery, typically six rats per test group are administeredthe test drugs by intraperitoneal (i.p.) injection or oral gavage. Fori.p. injection, the compounds are formulated in approximately 10 to 50%DMSO and given in a volume of 1 ml/kg body weight.

Tactile allodynia is measured prior to and 30 minutes after drugadministration using von Frey hairs that are a series of fine hairs withincremental differences in stiffness. Rats are placed in a plastic cagewith a wire mesh bottom and allowed to acclimate for approximately 30minutes. The von Frey hairs are applied perpendicularly through the meshto the mid-plantar region of the rats' hindpaw with sufficient force tocause slight buckling and held for 6-8 seconds. The applied force hasbeen calculated to range from 0.41 to 15.1 grams. If the paw is sharplywithdrawn, it is considered a positive response. A normal animal willnot respond to stimuli in this range, but a surgically ligated paw willbe withdrawn in response to a 1-2 gram hair. The 50% paw withdrawalthreshold is determined using the method of Dixon, W. J., Ann. Rev.Pharmacol. Toxicol. 20:441-462 (1980). The post-drug threshold iscompared to the pre-drug threshold and the percent reversal of tactilesensitivity is calculated based on a normal threshold of 15.1 grams. Theresults are expressed in per cent (%) MPE, where the MPE value reflectsthe percentage reversal of pain threshold to that of a normal animal(100%).

TABLE 3 Activity of Compounds in Chung Model of Neuropathic Pain (% PainReversal ± SEM) Dose and Route of Administration 1 μg/kg 3 μg/kg 10μg/kg 30 μg/kg 100 μg/kg 300 μg/kg 1000 μg/kg Compd. i.p. i.p. i.p. i.p.i.p. i.p. i.p. 1S & 0.8 ± 1.9  44 ± 6.3* 69 ± 15*  65 ± 11* 80 ± 9.4* 81± 10* 1R 1S 0.7 ± 0.8* 59 ± 5.8* 74 ± 6.1* 69 ± 10* 10 μg/kg 30 μg/kg100 μg/kg 300 μg/kg 1000 μg/kg Compd. p.o. p.o. p.o. p.o. p.o. 1S & 1R 2± 0.6 81 ± 8.2* 87 ± 6.1* 96 ± 4.5* All measurements 30 min followingdrug administration. *p value <0.001 compared to pretreatment values.

The results shown in Table 3 illustrate that these compoundssignificantly alleviate allodynic pain, and based on these test and/oron the compounds ability to activate alpha_(2B) and/or alpha_(2C)adrenergic receptors in preference over alpha_(2A) adrenergic receptors,the compounds are expected to be useful as analgesics to alleviateallodynia and chronic pain.

SPECIFIC EMBODIMENTS, EXPERIMENTAL EXAMPLE E Method E: Procedure forPreparation2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Compound 1S and Compound 1R)

1-Tetralone (commercially available from Aldrich) (Intermediate E1, 1.24g, 8.5 mmol) and 4,5-imidazole carboxaldehyde (Formula 8, (0.82 g, 8.5mmol) were added to 8.5 mL of a 40% solution of H₂SO₄. The solution washeated for 24 h at 90 EC. After cooling to rt, the reaction was madebasic with excess concentrated NH₄OH. The mixture was extracted twicewith THF. The organic layers were combined and washed with brine. Theorganic layer was separated and dried over Na₂SO₄. The mixture wasfiltered and the filtrate concentrated under reduced pressure to afford˜2.2 g of a yellow solid2-(1H-imidazol-4-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one(Intermediate E3). The crude product (Intermediate E3) was suspended inethanol (100 mL) and a palladium on carbon catalyst (10%, 0.27 g) added.The mixture was shaken in a Parr hydrogenator apparatus while under 40psi of hydrogen. After 19 h the reaction mixture was filtered throughCelite and the filtrate concentrated under reduced pressure. Columnchromatography with 5-7% MeOH:CHCl₃ afforded ˜0.9 g (45%) of a solidcomprising 2-(1H-imidazol-4-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one(Intermediate E4). The synthesis of2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Intermediate E5) was completed by subjecting the imidazole(Intermediate E4) to the conditions described in Method A for Example Afor the conversion to the thione (Intermediate E5 ).

¹H NMR (500 MHz, DMSO-d⁶ w/TMS) δ 11.9 (s, 1H), 11.7 (s, 1H), 7.88 (d,J=7.5 Hz, 1H), 7.57-7.54 (m, 1H), 7.37-7.34 (m, 2H), 6.58 (s, 1H),3.08-2.97 (m, 2H), 2.86-2.85 (m, 1H), 2.43 (dd, J=9.0, 6.0 Hz, 1H), 2.08(dd, J=4.0, 4.5 Hz, 1H), 1.1 (brs, 1H).

The racemic2-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one(Intermediate E5 ) was separated by chiral HPLC using a ChiralPak AD4.6×220 mm (Daicel Chem. Ind. Ltd.) with isocratic flow 1.2 mL/m, 10%isopropyl alcohol in acetonitrile mobile phase at 20 EC and UV 210 nm.The first peak with 6.5 min. retention time gave Compound 1S (−) S with[α]_(D) ²⁰−66.4 (c=0.57 in 9% DMSO:MeOH). The second fraction at 14.0min. gave Compound 1R (+) R with [α]_(D) ²⁰+61.9 (c=0.63 in 10%DMSO:MeOH). The absolute stereochemistry of Compounds 1S and 1R, asshown in the scheme, was assigned by derivatization followed by X-raycrystallography.

1. A method of alleviating pain in a mammal in need of such activationby administering to the mammal a pharmaceutical composition containing atherapeutically effective dose of the following compound


2. A method in accordance with claim 1 where the pharmaceuticalcomposition is administered to the mammal to alleviate chronic pain. 3.A method in accordance with claim 1 where the pharmaceutical compositionis administered to the mammal to alleviate allodynia.
 4. A method inaccordance with claim 1 where the pharmaceutical composition isadministered orally.
 5. A method in accordance with claim 1 where thepharmaceutical composition is administered intraperitionally.